The Genetic Architecture of Leukoaraiosis and Cognitive Function.

Abstract

Uncontrolled hypertension gives rise to arteriosclerotic target organ damage of the brain, heart, and kidneys. Ischemic brain injury due to hypertension is associated with clinical endpoints such as stroke and dementia. Subclinical measures of hypertension-related brain injury, such as leukoaraiosis (white matter hyperintensity on magnetic resonance imaging), are powerful predictors of stroke and dementia that aggregate in families and are likely to be the consequence of complex interactions between many genetic and environmental factors. Understanding the genetic architecture of leukoaraiosis may provide new insights into the etiology of the disease process and may help identify individuals that are at increased risk of developing stroke and dementia.

In this dissertation, both a candidate gene association study and a genome-wide association study were used to investigate the genetic architecture of leukoaraiosis in the white and African American cohorts of the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Since the genetic component of inter-individual variation in leukoaraiosis is likely to involve multiple loci that act alone or through interactions with other genetic or environmental factors, we also explored interactions between pairs of single nucleotide polymorphisms (SNPs) and between SNPs and traditional risk factors. Finally, given that stroke and dementia are both associated with hypertension-related brain injury, we investigated the extent of pleiotropy between leukoaraiosis and seven measures of cognitive function using both biometrical and measured genetic approaches. A greater understanding of the underlying genetic architecture of leukoaraiosis has the potential to provide insight into the etiological processes of stroke and dementia and to assist in earlier identification of individuals at increased risk for disease, the development of more efficacious treatments, and the tailoring of particular treatments to people most likely to respond positively.